tbuckley/cabot-search huggingface dataset:
RADT-02. WHOLE-BRAIN RADIATION THERAPY WITH SIMULTANEOUS INTEGRATED BOOST VERSUS STEREOTACTIC RADIOTHERAPY FOR THE TREATMENT OF BRAIN METASTASIS FROM NON-SMALL CELL LUNG CANCER
Authors: Wu Ziwei, Lu Lixia, Chen Yuanyuan, Chen Ming
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE To compare whole-brain radiotherapy with a simultaneous integrated boost (WBRT-SIB) to stereotactic radiotherapy (SRT) in treating non-small cell lung cancer (NSCLC) patients with brain metastases (BMs). METHODS Between April 2013 and June 2021, NSCLC patients receiving WBRT-SIB or SRT for 1-10 BMs were reviewed. Propensity score matching was carried out without replacement using a ratio of 1 WBRT-SIB: 1 SRT patient and a caliper width of 0.03 to yield sufficient power and homogeneity between treatment groups. Intracranial progression-free survival (iPFS), overall survival (OS), the cumulative incidence of local tumor progression, and intracranial distant tumor progression were compared between groups. Toxicities were assessed utilizing the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). RESULTS A cohort of 181 patients with was included in this study. After propensity score matching, there were 37 patients in the WBRT-SIB and the SRT group, respectively. The WBRT-SIB group had a significantly longer median iPFS than the SRT group (10.8 months vs. 6.5 months, p = 0.018). The median OS (p = 0.861) and the cumulative incidence of local tumor progression (p = 0.437) were similar between the two groups. WBRT-SIB was associated with reduced intracranial distant tumor progression (p = 0.043). No toxicities higher than grade 3 were observed in both groups. KPS score was an independent prognostic factor of OS (HR 0.459, p = 0.032). CONCLUSIONS Compared to SRT, the iPFS of NSCLC patients with BMs was prolonged after WBRT-SIB, mainly related to better control of distant intracranial tumors. WBRT-SIB is safe and can be an alternative option for patients with BMs. We also found that the KPS score is an independent prognostic factor of OS.
NCMP-04. INITIAL REPORT OF BOSWELLIA SERRATA FOR MANAGEMENT OF CEREBRAL RADIATION NECROSIS AFTER STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES
Authors: Rituraj Upadhyay, Ahmed Nader Mohammed Elguindy, Soma Sengupta, Kyle Wang, Sasha Beyer, Evan Thomas, Raju Raval, Joshua Palmer
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Radiation necrosis(RN) is a concerning late toxicity after radiation therapy(RT) for brain metastases(BM). Oral corticosteroids are the mainstay of management; however, not optimal given multiple side effects, particularly with the emergence of immunotherapy. Boswellia serrata(BS) is an over-the-counter supplement shown to reduce cerebral edema after brain RT. We evaluated the response rates with BS in a series of BM patients treated with stereotactic radiosurgery(SRS) who developed RN. METHODS We enrolled patients who developed RN after SRS for BM from 2020-2022 and were treated with BS 4.2-4.5g daily. Response was assessed using Response Assessment in Neuro-Oncology(RANO) criteria. Primary endpoint was ≥25% decrease in edema volume on T2-FLAIR MRI from baseline. RESULTS Fifty patients received BS for Grade 1-3 CTCAE v5.0 RN (G1=11, G2=36, and G3=3). Median time to RN was 10 months(m) after SRS and median follow-up was 6m. Best response was a complete response(CR) in 15% patients and partial response(PR) in 40% while 35% had stable disease(SD) and 10% had progression. At 3 , 6 , 9 and 12 months of follow-up respectively, 25%, 60%, 43% and 50% patients had any response(CR or PR). About 56% patients had symptomatic RN, of which 35.7% had improvement in symptoms with BS alone, while 64% required steroid use. Overall, median duration of response in patients with CR, PR or SD was 7.5m(range 2-31m). Salvage treatment for RN was steroids(33), surgery(4), Bevacizumab(5) or hyperbaric oxygen(1). No patient had ≥ CTCAE grade 3 toxicities, while 6% had grade 1-2 gastrointestinal intolerance. Overall, 39 patients remained on BS at last follow-up or death. CONCLUSION We observed &amp;gt; 50% response rates with use of BS in patients with grade 1-3 RN after SRS. Over 1/3rd patients with symptomatic RN were able to avoid long-term steroid use. Further prospective studies comparing Boswellia with placebo are warranted.
CTNI-22. A PHASE 0/2 ‘TRIGGER’ TRIAL OF NIRAPARIB IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA
Authors: Nader Sanai, Tigran Margaryan, Jennifer Molloy, Hualin Zhang, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, William Kennedy, Kelly Braun, Michael Garcia, Igor Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met. METHODS Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] &amp;gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors and positive PK were eligible for phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. RESULTS All phase 0 patients (n = 44) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 226.7 nM (n = 38). PAR suppression after ex vivo radiation was observed in 71% of the patients (20/28). Eighteen out of 26 patients with unmethylated tumors enrolled in phase 2. Five of the 18 initial patients in phase 2 experienced grade 4 thrombocytopenia related to niraparib. All adverse events were resolved without sequelae. For patients who completed at least 6 months of follow-up, PFS6 was 64% (n = 11) with 9.2-month median follow-up. Median follow-up for all patients (n = 18) was 4.2 months with 8 patients remaining on treatment and 2 patients ongoing PFS6 follow-up. CONCLUSIONS Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.
DDDR-22. PREDICTING AND TARGETING CLONALLY EXPANDING, TMZ-RESISTANT TUMOR CELLS IN GLIOBLASTOMA
Authors: Vivien Ullrich, Sarah Ertmer, Pia Berger, Sarah Langer, Anna Baginska, Hanah Gull, Madeleine Dorsch, Igor Cima, Celia Dobersalske, Sied Kebir, Martin Glas, Laurèl Rauschenbach, Ulrich Sure, Alexander Roesch, Barbara M Gruener, Björn Scheffler
Journal: Neuro-Oncology (2023)

Abstract Emerging evidence supports the notion that phenotypic plasticity contributes to disease progression and drug resistance in malignant glioma. We have recently described a rare population of ALDH1A1+ tumor cells in newly diagnosed, treatment-naive glioblastoma that can adapt to the exposure of the standard chemotherapeutic temozolomide (TMZ). Their subclonal growth leads to AKT-driven, TMZ-resistant cellular hierarchies. Accumulation of ALDH1A1+/pAKT+ cells can therefore be noted subsequent to TMZ in patient relapse tissue and in PDX models of disease. We have also shown that this series of events requires a sequential targeting approach where these subclones are allowed to enrich under TMZ and, only in a second step, are treated with AKT inhibitors. This “enrich and kill” strategy doubles the TMZ-based survival benefit in preclinical PDX models (Kebir et al., Clin Cancer Res 2023). Here, we took advantage of short-term expanded patient-derived cell cultures, which allow the study of early stages of this type of adaptive plasticity in controlled conditions. Specifically, we characterized the human lysine-specific demethylase 5B (KDM5B) as a prospective indicator for subclonal expansion in rare cells under first-time exposure to TMZ. We used genetic reporters, pharmacological interference, CHIP-seq analysis and cellular barcoding to investigate the dynamics of KDM5B expression and the related intracellular cross-signaling. We monitored patient cell samples over prolonged periods of time, and we found that KDM5Bhigh treatment-naive glioblastoma cells preferentially contribute to the dynamics of ALDH1A1 subclones and drug resistance under the influence of TMZ. These findings may lay ground for the development of biomarker-assisted clinical trials. This work is supported by DFG/GRC-CRU337/2 (proj#405344257).
BIOM-25. IDENTIFICATION OF PLASMA-DERIVED PREDICTIVE BIOMARKERS INCLUDING SERPINA3 FOR GLIOMA AND GLIOBLASTOMA
Authors: Manina Etter, Wandrille Duchemin, Tala Shekarian, Célia Durano, Julian Vogel, Marie-Françoise Ritz, Gregor Hutter
Journal: Neuro-Oncology (2023)

Abstract Advancement in the diagnosis and surveillance of gliomas has been limited posing both diagnostic and therapeutic challenges. Definitive diagnosis, distinction of progression versus pseudoprogression and prognosis assessment still depend on invasive neurosurgical biopsy procedure. Minimally-invasive plasma sampling could minimize the risks associated with invasive tissue sampling. Therefore, we aimed to identify specific plasma protein patterns of low- and high-grade glioma patients, compared to healthy individuals and investigated whether different plasma-derived protein signatures were associated with survival in glioma patients. Plasma samples were from patients with glioma grades I to IV collected during tumor removal and from healthy controls donating blood were processed for Liquid Chromatography Mass Spectrometry (LC/MS) proteomics after depletion of the 14 most abundant plasma proteins, in order to specifically detect low-abundant tumor-derived proteins. Overall, 646 proteins were measured across 104 plasma samples from glioma patients and 57 plasmas from the healthy cohort. PCA showed 2 clusters of samples, one containing low- and high-grade glioma samples and the other containing healthy and some grade IV (GBM) plasma samples. Interestingly, a spatial analysis of tumor location by MRI associated the GBM samples separated from healthy samples with subventricular vicinity. 26 differentially expressed proteins (DEPs) were identified discriminating between glioma and healthy samples and 30 DEPs discriminating GBM and healthy samples. The top most overexpressed proteins in gliomas vs controls were SERPINA3, F13A1, and TKT. Multivariate analysis identified SERPINA3, PPBP and MYH9 as strong discriminators of healthy vs GBM but also of low-grade vs GBM, indicating that these proteins may represent specific plasma biomarkers for GBM. SERPINA3, MYL1 and CLU were associated with poor survival in GBM. In conclusion, we describe sets of plasma derived proteins, in particular SERPINA3, as predictive biomarkers that could be used to assess tumor progression allowing patient-centered treatment options.
PATH-44. INTRA-OPERATIVE ANALYSES OF GENETIC ALTERATIONS IN THE CENTRAL NERVOUS SYSTEM TUMORS USING RAPID QUANTITATIVE PCR DEVICE
Authors: Fumiharu Ohka, Sachi Maeda, Junya Yamaguchi, Hiroki Shimizu, Kazuya Motomura, Kazuhito Takeuchi, Yuichi Nagata, Tomohide Nishikawa, Yuji Kibe, Yuhei Takido, Ryuta Saito
Journal: Neuro-Oncology (2023)

Abstract Recent comprehensive molecular analyses of central nervous system (CNS) tumors identified several diagnostic or prognostic markers. IDH mutation, TERT promoter (pTERT) mutation and CDKN2A homozygous deletion in adult-type diffuse gliomas, BRAF p.V600E mutation in circumscribed astrocytic gliomas, histone H3 gene mutations in pediatric-type diffuse high-grade gliomas or MYD88 mutation in primary CNS lymphoma (PCNSL) are quite important markers. Intra-operative identification of these molecular alterations could be effective for decision-making of tumor removal strategy. In this study, we established intra-operative gene analysis method using rapid quantitative PCR device, GeneSoC, by which we could obtain genotype of these important genes for 20 minutes in an operating room. Using GeneSoC, we could perform 50 cycles of quantitative PCR for approximately 12 minutes. We established rapid gene analyses of mutations of IDH1 p.R132H, pTERT C225T, pTERT C250T, H3 K27M, BRAF p.V600E and homozygous deletion of CDKN2A for diffuse gliomas and circumscribed astrocytic tumors and MYD88 p.L265P for PCNSL. For elution of DNA, we incubated at least 1mg of tumor tissue at 95°for 5 minutes. Combined this boiling method with GeneSoC, we could obtain those genetic alterations for 20 minutes after collection of tumor tissue. For 42 glioma cases and 10 PCNSL cases, we could obtain accurate genetic alterations (IDH1 p.R132H, pTERT C225T, pTERT C250T for gliomas or MYD88 p.L265P for PCNSL) in all cases, using this method. For detection of CDKN2A homozygous deletion, sensitivity and specificity are 100% and 83% in analyzed 50 cases, respectively. In this study, we could obtain the genotype of important molecular markers intra-operatively, not only during tumor removal but even during tumor biopsy, using GeneSoC device. This rapid genetic analysis might be effective not only for intra-operative diagnosis but also for detection of boundary between tumor and normal tissue.
CTNI-06. RHENIUM (RE-186) OBISBEMEDA{RE-186-NANOLIPOSOME (186RNL)} IN LEPTOMENINGEAL METASTASES [LM] PHASE 1/2A DOSE ESCALATION TRIAL: INITIAL SAFETY AND FEASIBILITY
Authors: Andrew Brenner, Michael Youssef, Priya Kumthekar, Joel Michalek, Marc Hedrick, Ande Bao, William Phillips, Toral Patel, Jeffrey Weinberg, John Floyd, Norman LaFrance
Journal: Neuro-Oncology (2023)

Abstract CONCLUSIONS: Adjuvant MHT may induce tumor radio-sensitization, immune cell recruitment, and survival benefit when combined with CRT. Optimization of the combination therapy treatment scheme is required.
NCMP-02. BIOPSY OUTCOMES OF PATIENTS WITH SUSPECTED LEPTOMENINGEAL CARCINOMATOSIS: A RETROSPECTIVE CASE SERIES
Authors: Audrey Blazek, Ivan Carabenciov
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leptomeningeal carcinomatosis is commonly considered when patients present with meningeal enhancement on magnetic resonance imaging (MRI), even without a known primary malignancy. In practice, some clinicians advocate for early meningeal biopsy to expedite diagnosis, citing lack of specificity of other testing, such as cerebrospinal fluid (CSF) analysis. METHODS We identified a cohort of patients with meningeal enhancement that underwent biopsy for diagnostic purposes between 2010 and 2022. Presenting symptoms, physical exam, enhancement pattern on MRI, other imaging findings, CSF parameters, other laboratory results, final diagnosis, and recommended treatment were recorded when available. RESULTS Out of nearly 100 cases included, the majority were autoimmune or inflammatory in etiology. Only 13 patients were diagnosed with malignancy-related enhancement, and 10 of these cases were felt to be true carcinomatosis. Nine out of the 13 patients were diagnosed with lymphoma. Four of these lymphomas were diagnosed on systemic biopsy, with meningeal biopsies negative for malignant cells. The other malignancies included systemic adenocarcinoma, oligodendroglioma, and a rare hematologic cancer. Nearly all 13 patients had abnormal CSF parameters, notably pleocytosis, but none had malignant cells in the fluid. Most frequent presenting symptoms were encephalopathy, vision changes, and strength/sensory changes. MRI often showed cranial nerve or general cerebral and cerebellar involvement, and physical exam often showed cranial nerve, strength, and sensory deficits. All patients proceeded with chemotherapy after diagnosis. CONCLUSIONS When leptomeningeal carcinomatosis is considered based on MRI enhancement, the clinical approach should continue to revolve around indirect testing such as CSF analysis, serum studies, and other imaging techniques to consider alternative biopsy sites before pursuing direct sampling with meningeal biopsy. With this approach, many patients with suspected carcinomatosis can avoid undergoing meningeal biopsy and decrease the chance of treatment delay.
RADT-51. RADIATION-INDUCED CEREBRAL CONTRAST ENHANCEMENTS STRONGLY SHARE RISK FACTORS WITH STROKE
Authors: Tanja Eichkorn, Jonathan Lischalk, Robert Schwarz, Lena Jasmin Bauer, Maximilian Deng, Sebastian Regnery, Christine Jungk, Klaus Herfarth, Laila König, Jürgen Debus
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND AND PURPOSE Radiation-induced cerebral contrast enhancements (RICE) are feared because frequent and potentially health-threatening. Risk factors are badly understood. Better understanding of RICE risk factors is critical to better face its risks by adapting therapy in the first place or patient care during follow-up. MATERIALS AND METHODS We analyzed consecutive 235 patients treated with proton radiotherapy (PRT; 54Gy RBE) for LGG from 2010 to 2020 and followed with serial clinical exams and magnetic resonance imaging for in median 5.6 years. RESULTS The risk of RICE was significantly higher in patients with vascular risk factors (VRF) (p = 0.02). Especially age ≥50 years (vs. adults &amp;lt;50 years: two-fold risk; p = 0.02), hypertension (three-fold risk; p = 0.0001) and diabetes (6.7-fold risk; p = 0.007) were shown to be clearly associated to RICE occurrence. Dyslipidemia (2.4-fold), overweight (1.3-fold) and smoking (1.3-fold) was also more frequently observed in the cohort that developed RICE. History of previous stroke went along with a 1.7-fold risk for RICE but threshold for significance was not reached. If RICE occurred, Bevacizumab treatment was two-fold more frequently needed in the cohort with VRF, but RICE prognosis did not differ relevantly between the RICE subcohort with and without VRF. CONCLUSIONS These data firstly demonstrate that RICE strongly share risk factors with ischemic stroke which further enhances our vague understanding of multifactorial pathophysiology and opportunities of tackling RICE. Classical vascular risk factors, especially age, hypertension and diabetes correlated strongly with RICE risk. Risk-adapted screening and therapy can be directly derived from this data.
CNSC-18. DIFFERENTIAL EFFECTS OF NEUROTRANSMITTERS ON THE GROWTH OF GLIOBLASTOMA SUBTYPES
Authors: Khushboo Irshad, Sanjay Singh, Khalil Ali Ahmad, Ben Aghoghovwia, Sama Alnassiry, Frederick Lang, Yuan Pan
Journal: Neuro-Oncology (2023)

Abstract Glioblastomas are aggressive brain tumors associated with the worst patient prognosis. Neurons play critical roles in modulating the growth of glioblastoma. It has been demonstrated that glutamatergic neurons form bona fide synapses with glioblastoma tumor cells that are critical for tumor cell proliferation and migration. It is less clear whether the activity of other neuronal types influences glioblastoma pathophysiology, especially among the different glioblastoma molecular subtypes. Here, we examined the effects of neurotransmitters on the growth of glioblastoma cells characterized as the classical, proneural and mesenchymal subtypes. Patient-derived glioblastoma cell lines were exposed to varying concentrations of different neurotransmitters for 72 hours and assessed for cell viability using the CCK-8 assay. RESULTS: from the CCK8 assay indicate that acetylcholine and dopamine increase glioblastoma cell growth. Consistent with previous findings, we observed an increase in cell viability in all cell lines after being incubated with L-glutamate. The classical subtype has a stronger growth response to L-glutamate compared to the other two subtypes. Transcriptomic data from TCGA showed that the expression of GRIK4 (glutamate ionotropic receptor kainate type subunit 4) is the highest in the classical subtype. By comparing GRIK4 expression with patient survival in TCGA glioblastoma cases stratified by molecular subtypes, we found that high GRIK4 expression correlates with worse prognosis in the classical subtype, but not the proneural or mesenchymal patient groups. Our findings suggest that each glioblastoma subtype may differentially leverage neuromodulatory mechanisms to support their own growth. Ongoing studies are investigating the differential neuronal responses in glioblastoma subtypes using both pharmacological and genetic approaches.
EPCO-22. LONGITUDINAL MOLECULAR CHARACTERIZATION IDENTIFIES TREATMENT DRIVEN EVOLUTION OF OLIGODENDROGLIOMA
Authors: Tamrin Chowdhury, Kevin Johnson, Emre Kocakavuk, Chaewon Heo, Gordon Y Ye, Padmaja Ghospurkar, Taylor Wade, Jill Barnholtz-Sloan, Joseph Costello, Carol Elliott, Pim French, Anna Golebiewska, Beth Hermes, Chibo Hong, Craig Horbinski, Mustafa Khasraw, Peter LaViolette, Kay Ka-Wai Li, Eric Lipp, Allison Lowman, Katy McCortney, Hyo-Eun Moon, Ho-Keung Ng, Marta Padovan, Sun Ha Paek, Wies Vallentgoed, Rachael Vaubel, Pieter Wesseling, Kerryn Westcott, Frederick Varn, Roel Verhaak
Journal: Neuro-Oncology (2023)

Abstract Oligodendroglioma is characterized by oligodendrocyte-like histology, mutation in the IDH genes, along with codeletion of chromosome arms 1p and 19q. Treatment for oligodendrogliomas combines surgery, followed by observation, and chemotherapy and/or radiotherapy when tumors progress. Most oligodendrogliomas eventually recur with a more aggressive phenotype, leading to patient mortality but molecular mechanisms remain poorly understood. To investigate the molecular trajectory of oligodendroglioma, we collected more than 270 longitudinal samples from over 130 oligodendroglioma patients, to perform whole genome or whole exome sequencing, bulk RNA, and single-nucleus RNA sequencing (n = 30 samples). Common mutations in IDH1/2, TERT promoter, CIC, and FUBP1 were observed. About half of the CIC and FUBP1 mutations occurred in the initial sample and persisted stably throughout recurrence. The majority of PIK3CA and PIK3R1 mutations were either shared or present in recurrences only implicating the PI3K pathway in oligodendroglioma recurrence. Mutational signature analysis revealed 34.5% of tumors treated with alkylating agents acquired SBS11/SBS31 associated hypermutation. By integrating signatures with clonality estimates, we approximated the timing of mutational processes and found that clonal timings of treatment related mutations correlate with the treatment administration date. We found that aging signature-related mutations were mostly clonal, and treatment signature-related mutations were more likely to be sub-clonal, supporting the late emergence of these mutations following treatment. We observed increased somatic copy number alterations in oligodendroglioma recurrences, reflected in notable chromosome 4 losses. Associating treatment with snRNAseq derived cellular states, we observed a significant increase in the fraction of proliferating stem-like cells in the hypermutator versus non-hypermutator recurrent samples. These findings shed light on the molecular changes occurring in oligodendrogliomas following treatment and provide insights that may aid in targeting treatment resistance.